Ann Thorac Surg 2002;73:862-865
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Effects of dilutional and modified ultrafiltration in plasma endothelin-1 and pulmonary vascular resistance after the Fontan procedure
Takeshi Hiramatsu, MD*a,
Yasuharu Imai, MDa,
Hiromi Kurosawa, MDa,
Yoshinori Takanashi, MDa,
Mitsuru Aoki, MDa,
Toshiharu Shin'oka, MDa,b,
Makoto Nakazawa, MDb
a Department of Cardiovascular Surgery, Division of Pediatric Cardiac Surgery, Tokyo Women’s Medical University, Heart Institute of Japan, Tokyo, Japan
b Department of Cardiology, Division of Pediatric Cardiology, Tokyo Women’s Medical University, Heart Institute of Japan, Tokyo, Japan
Accepted for publication November 15, 2001.
* Address reprint requests to Dr Hiramatsu, Department of Cardiovascular Surgery, Tokyo Women’s Medical University, Heart Institute of Japan, 8-1 Kawada-cho, Shinjuku-ward, Tokyo, 162-8666 Japan
e-mail: shiramat{at}hij.twmu.ac.jp
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Abstract
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Background. Pulmonary vascular resistance (PVR) is closely related with patients’ hemodynamics after the Fontan procedure and endothelin-1 (ET-1) may play an important role in pulmonary circulation. Modified ultrafiltration (MUF) is known to remove inflammatory mediators after cardiopulmonary bypass (CPB) surgery. The time courses of plasma ET-1 and PVR were examined before and after the Fontan procedure with MUF.
Methods. Twenty-two patients who underwent the Fontan procedure were divided into two groups: a dilutional ultrafiltration/modified ultrafiltration (DUF/MUF) group (n =11) and a control group (n = 11). Conventional ultrafiltration was performed during CPB in the control group. DUF was performed semicontinuously during CPB and MUF was continued until 15 to 20 minutes after the CPB with polyacrylonitonile membrane in the DUF/MUF group. The plasma ET-1 concentration was mea-sured before and after CPB, after MUF in the DUF/MUF group, and 6 and 24 hours after CPB. PVR was calculated simultaneously using a thermodilutional catheter.
Results. Plasma ET-1 levels increased significantly after CPB in the control group but they did not increase immediately after CPB in the DUF/MUF group. Similarly, PVR increased significantly after CPB in the control group but it did not increase after CPB in the DUF/MUF group and remained low at 6 and 24 hours after CPB.
Conclusions. DUF and MUF suppress the increase in the plasma ET-1 concentration that occurs immediately after the completion of the Fontan procedure and may be an effective intervention for maintaining low PVR after the procedure
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Introduction
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Recently the Fontan procedure has been extended to more complex congenital heart defects with greater risk factors and higher potential for complications. Pulmonary factors, especially pulmonary vascular resistance (PVR), are critical for determining whether the Fontan procedure is indicated in a particular case [1, 2]. Recent evidence suggests that pulmonary vascular tone is regulated by a complex interaction of vasoactive substances that are locally produced by the vascular endothelium [3]. Cytokines, which influence pulmonary circulation, seem to affect a patient’s hemodynamics after the Fontan procedure has been performed [4]. Endothelin-1 (ET-1) is a 21-amino acid polypeptide produced by vascular endothelial cells. Prior studies suggest that the endothelium-derived vasoconstrictor ET-1 may be involved in the pathophysiology of pulmonary hypertension [5]. We have already shown that plasma ET-1 levels increase after the Fontan procedure has been performed and that a significant positive correlation exists between plasma ET-1 levels and PVR after the Fontan procedure [4].
Modified ultrafiltration (MUF) has been used to reverse the hemodilution that occurs during cardiac operations. Recent studies have demonstrated that some low molecular weight inflammatory mediators including ET-1 (2.5 kDa) can be removed by hemofiltration during cardiopulmonary bypass (CPB) [6, 7]. Recently this MUF technique was applied during pediatric open-heart operations and was shown to be effective for reducing the adverse effects of CPB in pediatric patients [6–9]. However, the effects of MUF on plasma ET-1 levels and PVR after the Fontan procedure have not been studied. We measured the time course of plasma ET-1 levels with or without MUF and tested the hypothesis that the removal of plasma ET-1 by MUF might reduce PVR in patients who have undergone the Fontan procedure for the treatment of complex congenital heart disease.
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Patients and methods
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Patients
Twenty-two children with congenital heart disease who underwent the Fontan procedure (connection of the right atrial appendage to the pulmonary artery) were assigned to one of two groups as follows: the control group (n = 11; tricuspid atresia 1, double outlet right ventricle 4, transposition of great arteries with pulmonary stenosis 1, single right ventricle 4, single left ventricle 1) who received conventional hemofiltration during CPB; and the dilutional ultrafiltration/modified ultrafiltration (DUF/MUF) group (n = 11; single right ventricle 3, single left ventricle 2, tricuspid atresia 3, double outlet right ventricle 2, pulmonary atresia with intact ventricular septum 1) who received DUF during CPB and MUF after CPB. The preoperative diagnosis and patient characteristics for each group are shown in Table 1. No significant differences were observed between the groups with respect to diagnoses and demographics. The children were aged from 1 to 14 years old and no significant differences in mean age or body weight were present between the two groups. No significant differences in preoperative hemodynamic indices such as mean pulmonary arterial pressure (mPAP), mean pulmonary wedge pressure (Pw), or cardiac index (CI) were present between the two groups (Table 1).
Study protocol
Anesthesia was induced by intravenous infusion of diazepam (0.2 mg/kg) with muscle relaxants, and fentanyl was used for maintenance. No inhalation agents were used. Immediately before CPB mean pulmonary pressure and left atrial pressure were measured directly, and pulmonary blood flow was measured using a magnetic flow meter. PVR was then calculated. The inspiratory oxygen concentration was kept at 40% during the measurement. Conventional CPB was initiated with one episode of aortic crossclamping and multiple-dose cardioplegia (glucose-insulin-potassium solution). The circuit for CPB consisted of a pulsatile roller pump (TCW NCK component system; Tonokura, Tokyo, Japan) and a membranous oxygenator (VPCML; COBE Laboratories, Arvada, CO). The perfusion flow rate was regulated at 2.2 to 2.4 L ·1 m-2 ·1 min-1 with moderate hypothermia (rectal temperature of 28°C to 30°C). The hematocrit value was kept between 18% and 28% during CPB. Dopamine at a dose of 4 to 10 µg ·1 kg-1 ·1 min-1 was continuously infused after CPB. No nitroglycerin or nitroprusside was given during after CPB. No significant differences in CPB time or aortic crossclamping time occurred between the two groups (Table 1).
Conventional ultrafiltration
In the control group, the patients were treated using conventional ultrafiltration during CPB that removed any excess fluid and hemoconcentrated the patients’ blood using a hemoconcentrator (model HPH 400m; Minntech, Minneapolis, MN). Suction of 200 mm Hg negative pressure was applied to the filtrate port to maximize the filtration rate. The blood remaining in CPB circuit after termination of CPB was centrifuged with a cell separator and transfused back to the patients in operating room and intensive care units. The total amount of fluid filtered by conventional ultrafiltration was 25.3 ± 9.5 mL/kg.
Dilutional and modified ultrafiltration
A veno-venous DUF/MUF method was used in all of the patients in the DUF/MUF group. In this method, the patients’ femoral venous blood was drawn into the DUF/MUF circuit through the tip of a 6F single-lumen catheter inserted into a femoral vein and ultrafiltrated using a hemofilter with a polyacrylonitrile (PAN) membrane (APF-S; Asahi Medical, Tokyo, Japan). The PAN membrane has superior biocompatibility and sieving ability eliminating a low molecular weight protein. After ultrafiltration the filtration circuit blood was returned to the patients through another 6F single-lumen catheter inserted into the contralateral femoral vein. DUF was carried out continuously throughout CPB run and the patients’ blood was actively exchanged by removing fluid at a rate equivalent to the crystalloid cardioplegia volume plus 40 to 80 mL/kg per hour and adding small aliquots of diluent (Sublood B; Fuso Pharmaceutical, Osaka, Japan) as necessary to maintain a safe blood level in the reservoir of CPB circuit. MUF was continued until 15 to 20 minutes after the completion of CPB with an ultrafiltration rate of 100 to 150 mL/min. The total amount of fluid filtered by DUF and MUF was 52.6 ± 18.9 mL/kg and 134 ± 32.4 mL/kg, respectively.
Blood samples were taken from the central venous line before CPB (pre-CPB), immediately after CPB (post-CPB), after MUF (post-MUF) in the DUF/MUF group, and 6 and 24 hours after CPB. The blood samples were immediately placed in an ice box and the tubes of collected blood containing 7.5 mmol/L EDTA were centrifuged at 2000 x g for 10 minutes at 4°C. The plasma was immediately separated and stored at -70°C to minimize degradation. The plasma ET-1 concentration was measured using a commercially available ET-1, 21 specific radioimmunoassay system (SRL, Tokyo, Japan). The details of this methodology were previously described [4].
A thermodilutional catheter was introduced during the operation and CI, mPAP, and Pw were measured; PVR was then calculated at the same time points. The correlation coefficiency between the plasma ET-1 levels and PVR data were calculated using a least square regression equation.
Statistics
All values were expressed as mean ± SD. Data were compared using the two-tailed paired and Student’s t test or repeated-measures two-way analysis of variance. A p value less than 0.05 was considered to be significant.
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Results
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There was no operative death and all patients were extubated within several hours after the operation and the postoperative course was relatively smooth in all patients.
The time course of plasma ET-1 levels is shown in Figure 1.
The plasma ET-1 levels in the control group increased significantly after CPB compared with the pre-CPB values and peaked at 6 hours after CPB. On the other hand, the plasma ET-1 levels in the DUF/MUF group did not increase immediately after CPB but were elevated at 6 and 24 hours after CPB compared with the pre-CPB values. The difference in plasma ET-1 levels between the post-CPB value in the control group and the post-MUF value in the DUF/MUF group was statistically significant. In the DUF/MUF group, 3.4 ± 1.0 pg/mL of ET-1 was removed during DUF and MUF.
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Fig 1. The time course of the plasma endothelin-1 (ET-1) level. *p < 0.05 versus pre-CPB; #p < 0.05 versus control. The error bars are the standard deviation; the dashed line represents the control group; the solid line represents the MUF group. (CPB = cardiopulmonary bypass; MUF = modified ultrafiltration.)
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The time course of PVR is shown in Figure 2.
In the control group, PVR increased significantly after CPB compared with the pre-CPB value and peaked at 6 hours after CPB. On the other hand, PVR in the DUF/MUF group did not increase after CPB and remained unchanged at 6 and 24 hours after CPB. The difference in PVR values 6 hours after CPB was statistically significant between the two groups.
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Fig 2. The time course of the pulmonary vascular resistance (PVR). *p < 0.05 versus pre-CPB; #p < 0.05 versus control. The error bars are the standard deviation; the dashed line represents the control group; the solid line represents the MUF group. (CPB = cardiopulmonary bypass; MUF = modified ultrafiltration.)
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The correlation between plasma ET-1 levels and PVR data is given in Figure 3.
A significant positive correlation was obtained between the plasma ET-1 levels and the PVR data at each time points. The r value including all of the measurements throughout the 24 hours was 0.533 (p < 0.0001) and the highest r value was obtained at post-CPB (r = 0.734). Correlation between the plasma ET-1 levels and the values of other hemodynamic indices such as mPAP, Pw, or CI were not significantly correlated (data not shown).
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Comment
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Multiple hemodynamic factors have been examined to determine the proper indications and criteria for performing the Fontan procedure; PVR is one of the most important factors in making such a decision. Children who have undergone the Fontan procedure are particularly sensitive to elevations in PVR and decreases in pulmonary and ventricular compliance. Elevated PVR has been known to increase the risks of serious complications in patients who have undergone the Fontan procedure [1, 2]. Strategies to reduce PVR are thus necessary to induce better hemodynamics after the Fontan procedure.
Recent evidence suggests that pulmonary vascular tone is regulated by a complex interaction of vasoactive substances that are locally produced by the pulmonary vascular endothelium. Prior studies suggest that the endothelium-derived vasoconstrictor ET-1 may be involved in the pathophysiology of pulmonary hypertension [5]. Although the hemodynamic status after the Fontan procedure is dependent upon multiple factors, the plasma ET-1 concentration may play an important role in determining pulmonary vascular tone and may be one of the most important factors after the Fontan procedure. We have already shown that plasma ET-1 levels are elevated after the Fontan procedure has been performed; these elevated levels are significantly correlated with PVR [4].
Naik and associates [8] introduced the use of MUF as an alternative method to reduce the adverse effects of CPB in pediatric patients. Early studies on the use of MUF reported a decrease in the amount of total body water that accumulates after CPB, reductions in perioperative blood loss, and a decrease in blood use. Later studies demonstrated that MUF also reduced postbypass PVR [9]. Moreover, recent studies have demonstrated that in addition to plasma water, solutes of less than 50 kDa in size are removed during MUF, including a number of inflammatory mediators [6]. Therefore MUF can be expected to reduce plasma ET-1 levels and to maintain low PVR, improving the patients’ hemodynamics after the Fontan procedure has been performed. Koutlas and colleagues [10] showed that perioperative blood loss and blood use were significantly decreased and that there was a lower incidence of early postoperative pleural and pericardial effusions in patients who received MUF after the cavopulmonary connection but no previous study has focused on the effects of MUF on the plasma ET-1 levels and PVR values after the Fontan procedure. Moreover, the effects of DUF throughout CPB and MUF as long as 15 to 20 minutes after CPB have not been precisely examined. The results of the current study show that DUF and MUF suppress the increase in plasma ET-1 concentration that occurs immediately after the Fontan procedure and maintain postoperative PVR at a low value. These results suggest that DUF/MUF is an effective intervention for maintaining low PVR and improving patients’ hemodynamics after the Fontan procedure.
Although the plasma ET-1 level in the DUF/MUF group was low when measured post-CPB and post-MUF, it was elevated to almost the same level as the control group at 6 and 24 hours after CPB. This elevation is thought to be due to a vasoconstrictive mechanism compensating for the relatively low cardiac output status after the Fontan procedure. On the other hand, PVR in the DUF/MUF group remained low after CPB. Probably the initial suppression of plasma ET-1 by DUF and MUF may have a strong impact on pulmonary circulation, enabling PVR to be maintained at low level and improving the patients’ hemodynamics after the Fontan procedure.
Regarding the technique of veno-venous MUF, we used bilateral femoral vein catheters instead of a double-lumen catheter inserted into the right atrium. The advantages of this method are that MUF can be started smoothly after cessation of CPB and performed simultaneously while the chest is being closed. Although this technique seems invasive use of bilateral femoral veins for later cardiac catheterization, the femoral vein catheter prepared for MUF was removed immediately after the operation and we have never experienced occlusion of the femoral vein in this study.
These conclusions are limited by the possibility that other inflammatory mediators are removed during MUF, thereby influencing the pulmonary vascular tone after the Fontan procedure. Bradykinin may be another important factor affecting PVR after the Fontan procedure but was not measured in this study because of the volume of blood required. Therefore the correlation coefficient between the plasma ET-1 and PVR in this study was not so high (r = 0.533) and other variables such as bradykinin also might play an important role in regulating the pulmonary vascular tone.
In summary, the results of this study suggest that DUF and MUF suppress the increase in plasma ET-1 that occurs immediately after the completion of the Fontan procedure and that DUF/MUF is an effective intervention for maintaining low PVR after the procedure.
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References
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Abstract
Introduction
